Our reseach goal is to investigate pathophysiological roles of free radicals such as nitric oxide (NO.) and hydroxyl radical (.OH) in progressive degenerative brain disorders (i.e., Parkinson's disease, ischemia/ reperfusion brain injury, head trauma and Alzheimer's, senile or AIDS dementia). We employed animal models which were developed by our group and in vitro testing procedures to understand free radical chain reaction in causing oxidative brain injury. The outcome of this high- risk research may be used to further evaluate neuroprotective strategies and alternative treatments for slowing or halting the progressive deterioration in motor and cognitive degenerative brain disorders. We have provided relevant in vivo evidence to support our working hypothesis that reactive .OH but not NO. radicals are pro-oxidant and cytotoxic to brain neurons. Based on their relative reactivity, we demonstrated that NO. can suppress the generation of the more reactive .OH free radicals elicited by iron complexes, resulting in protection of brain neurons from oxidant injury. Antioxidant properties of NO. were conclusively demonstrated both in vivo and in vitro preparations. NO. or NO. donors (S-nitrosothiols) can suppress .OH generation and associated lipid peroxidation and brain injury catalyzed by submicromolar iron complexes. Significantly, S-nitrosoglutathione was more potent than the classical antioxidant glutathione. Cytotoxic .OH radicals can be generated in the basal ganglia through dopamine autoxidation and redox cycling of iron complexes which may lead to nigrostriatal degeneration and Parkinson's disease. Our new findings that atypical antioxidants (S-nitrosothiol NO. donors and manganese) and U-78517F protected substantia nigra dopaminergic neurons against oxidant injury caused by .OH may provide new insights for formulating alternative neuroprotective treatments. Although these neuroprotective studies were demonstrated in parkinsonian animal models, possible future clinical implications in other brain disorders caused by free radicals and associated oxidant stress remain to be elucidated.